RYK

Summary

RYK (receptor like tyrosine kinase, HGNC:10481) is a protein-coding gene on chromosome 3q22.2, encoding Tyrosine-protein kinase RYK (P34925). May be a coreceptor along with FZD8 of Wnt proteins, such as WNT1, WNT3, WNT3A and WNT5A.

The protein encoded by this gene is an atypical member of the family of growth factor receptor protein tyrosine kinases, differing from other members at a number of conserved residues in the activation and nucleotide binding domains. This gene product belongs to a subfamily whose members do not appear to be regulated by phosphorylation in the activation segment. It has been suggested that mediation of biological activity by recruitment of a signaling-competent auxiliary protein may occur through an as yet uncharacterized mechanism. The encoded protein has a leucine-rich extracellular domain with a WIF-type Wnt binding region, a single transmembrane domain, and an intracellular tyrosine kinase domain. This protein is involved in stimulating Wnt signaling pathways such as the regulation of axon pathfinding. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 6259 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 44 total
• MANE Select transcript: NM_002958

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10481
Approved symbol	RYK
Name	receptor like tyrosine kinase
Location	3q22.2
Locus type	gene with protein product
Status	Approved
Aliases	D3S3195, RYK1, JTK5
Ensembl gene	ENSG00000163785
Ensembl biotype	protein_coding
OMIM	600524
Entrez	6259

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 23 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay

ENST00000464879, ENST00000473208, ENST00000480381, ENST00000481382, ENST00000484106, ENST00000486725, ENST00000620660, ENST00000623711, ENST00000907584, ENST00000907585, ENST00000912303, ENST00000912304, ENST00000912305, ENST00000912306, ENST00000912307, ENST00000946529, ENST00000946530, ENST00000946531, ENST00000946532, ENST00000946533, ENST00000946534, ENST00000946535, ENST00000946536, ENST00000946537, ENST00000946538, ENST00000946539, ENST00000946540, ENST00000946541, ENST00000946542

RefSeq mRNA: 2 — MANE Select: NM_002958 NM_001005861, NM_002958

CCDS: CCDS75016, CCDS77820

Canonical transcript exons

ENST00000623711 — 15 exons

Exon	Start	End
ENSE00001239490	134195082	134195182
ENSE00001239498	134202730	134202874
ENSE00001957445	134157133	134158264
ENSE00003459677	134207472	134207525
ENSE00003558920	134209695	134209829
ENSE00003561619	134159237	134159373
ENSE00003565055	134211508	134211607
ENSE00003587184	134191849	134191974
ENSE00003599153	134183002	134183071
ENSE00003621361	134188837	134188923
ENSE00003632328	134222418	134222539
ENSE00003695782	134175930	134176039
ENSE00003697038	134177941	134178073
ENSE00003698594	134175609	134175768
ENSE00003901283	134250423	134250859

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 97.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.6332 / max 113.8635, expressed in 1807 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44688	17.7203	1797
44687	7.9130	1706

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.82	gold quality
calcaneal tendon	UBERON:0003701	97.69	gold quality
left ovary	UBERON:0002119	96.67	gold quality
ovary	UBERON:0000992	96.66	gold quality
saphenous vein	UBERON:0007318	96.62	gold quality
mucosa of stomach	UBERON:0001199	96.37	gold quality
urethra	UBERON:0000057	96.23	gold quality
ventricular zone	UBERON:0003053	96.16	gold quality
germinal epithelium of ovary	UBERON:0001304	96.14	gold quality
right ovary	UBERON:0002118	96.07	gold quality
stromal cell of endometrium	CL:0002255	96.05	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.73	gold quality
synovial joint	UBERON:0002217	95.70	gold quality
pericardium	UBERON:0002407	95.57	gold quality
tibia	UBERON:0000979	95.52	gold quality
colonic epithelium	UBERON:0000397	95.50	gold quality
vena cava	UBERON:0004087	95.42	gold quality
periodontal ligament	UBERON:0008266	95.34	gold quality
blood vessel layer	UBERON:0004797	95.09	gold quality
nipple	UBERON:0002030	95.02	gold quality
endocervix	UBERON:0000458	94.85	gold quality
cartilage tissue	UBERON:0002418	94.71	gold quality
body of uterus	UBERON:0009853	94.66	gold quality
vagina	UBERON:0000996	94.62	gold quality
adrenal tissue	UBERON:0018303	94.56	gold quality
mammary duct	UBERON:0001765	94.50	gold quality
penis	UBERON:0000989	94.47	gold quality
left uterine tube	UBERON:0001303	94.42	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.38	gold quality
lower esophagus	UBERON:0013473	94.37	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	10.95
E-ANND-3	yes	7.03
E-MTAB-6142	no	79.24
E-CURD-112	no	2.92

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ESR1, MYC, NFIA, NFKB1, WT1

miRNA regulators (miRDB)

105 targeting RYK, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-124-3P	99.89	73.74	3043

Literature-anchored findings (GeneRIF, showing 19)

• RYK, a catalytically inactive receptor tyrosine kinase, associates with EphB2 and EphB3 but does not interact with AF-6. (PMID:11956217)
• a missense mutation, 1355G>A, and one rare single nucleotide polymorphisms haplotype may play a role in the development of cleft lip and/or palate in the Vietnamese, and cleft lip and/ or palate and cleft palate only in the Japanese (PMID:16681403)
• validated occurrence of an unusual TG 3’ splice site in intron 7 (PMID:17672918)
• RYK interacts both physically and functionally with the E3 ubiquitin MIB1. MIB1 is sufficient to activate Wnt/CTNNB1 signaling and this activity depends on endogenous RYK. (PMID:21875946)
• RYK and VANGL2 proteins form a complex, whereas RYK also activated RhoA, a downstream effector of PCP signaling. (PMID:22773843)
• is a candidate wnt5a receptor. (PMID:23748645)
• The Ryk is important for the Wnt-5a-dependent induction of MMP-2 and invasive activity in glioma-derived cells and that Ryk might have a novel patho-physiological function in adult cancer invasion. (PMID:24621529)
• Ryk-intracellular domain pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting neurons unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in Huntington disease (PMID:24960609)
• Early treatment with HGF/IgG complexes after myocardial ischaemia with reperfusion may rescue tissue through vasoprotection conferred by c-Met and RYK signalling (PMID:26025956)
• results corroborated previous findings of Ryk-mediated Wnt5a effect, and suggested a role for Ror2 in the Wnt5a machinery in glioblastoma (PMID:26596412)
• Wnt5A/Ryk signaling might provide novel therapeutic strategies to prevent capillary leakage in systemic inflammation and septic shock. (PMID:27159116)
• our findings demonstrate that Ryk promotes stem cell-like and tumorigenic features to glioma cells its essential for the maintenance of glioblastoma stem cells (PMID:28086236)
• appears to signal predominantly through non-canonical WNT-triggered pathways including the PCP and WNT/Ca2+ pathways [review] (PMID:29806777)
• RYK is highly correlated with gastric cancer tumorigenesis and the potential of liver metastasis, suggesting it may be a novel oncogenic factor of the noncanonical Wnt signaling pathway (PMID:31869240)
• Structural Insights into Pseudokinase Domains of Receptor Tyrosine Kinases. (PMID:32619402)
• PAX7, PAX9 and RYK Expression in Cleft Affected Tissue. (PMID:34684112)
• WNT/RYK signaling functions as an antiinflammatory modulator in the lung mesenchyme. (PMID:35671428)
• Comprehensive analysis reveals COPB2 and RYK associated with tumor stages of larynx squamous cell carcinoma. (PMID:35715770)
• Downregulation of exosomal miR-7-5p promotes breast cancer migration and invasion by targeting RYK and participating in the atypical WNT signalling pathway. (PMID:36210461)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ryk	ENSDARG00000007231
mus_musculus	Ryk	ENSMUSG00000032547
rattus_norvegicus	Ryk	ENSRNOG00000008593
caenorhabditis_elegans		WBGENE00003007

Paralogs (53): INSRR (ENSG00000027644), MUSK (ENSG00000030304), FLT4 (ENSG00000037280), EPHA3 (ENSG00000044524), ROS1 (ENSG00000047936), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), EPHA6 (ENSG00000080224), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), EPHB2 (ENSG00000133216), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), ERBB2 (ENSG00000141736), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), MST1R (ENSG00000164078), LMTK2 (ENSG00000164715)

Protein

Protein identifiers

Tyrosine-protein kinase RYK — P34925 (reviewed: P34925)

All UniProt accessions (3): P34925, A0A0D9SFZ4, H7C4P6

UniProt curated annotations — full annotation on UniProt →

Function. May be a coreceptor along with FZD8 of Wnt proteins, such as WNT1, WNT3, WNT3A and WNT5A. Involved in neuron differentiation, axon guidance, corpus callosum establishment and neurite outgrowth. In response to WNT3 stimulation, receptor C-terminal cleavage occurs in its transmembrane region and allows the C-terminal intracellular product to translocate from the cytoplasm to the nucleus where it plays a crucial role in neuronal development.

Subunit / interactions. Interacts with DVL1 (via PDZ domain).

Subcellular location. Membrane. Nucleus. Cytoplasm.

Tissue specificity. Observed in all the tissues examined.

Post-translational modifications. Proteolytically cleaved, in part by presenilin, in response to WNT3 stimulation. Cleavage occurs during neuronal differentiation.

Domain organisation. The extracellular WIF domain is responsible for Wnt binding.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P34925-1	1	yes
P34925-2	2

RefSeq proteins (2): NP_001005861, NP_002949* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR003306	WIF	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR038677	WIF_sf	Homologous_superfamily
IPR050122	RTK	Family

Pfam: PF02019, PF07714

Enzyme classification (BRENDA):

• EC 2.7.10.1 — receptor protein-tyrosine kinase (BRENDA: 44 organisms, 214 substrates, 574 inhibitors, 11 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0011–0.129	4
AC-DYFE-6-CHLORO-W-NHME	0.0051	1
AC-DYFGW-NHME	0.07	1
YFEW	0.232	1

Catalyzed reactions (Rhea), 1 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (65 total): helix 18, sequence conflict 11, strand 7, glycosylation site 5, sequence variant 3, mutagenesis site 3, binding site 2, topological domain 2, turn 2, domain 2, region of interest 2, signal peptide 1, chain 1, active site 1, modified residue 1, disulfide bond 1, splice variant 1, transmembrane region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6TUA	X-RAY DIFFRACTION	2.38

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P34925-F1	80.54	0.60

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 465 (proton acceptor)

Ligand- & substrate-binding residues (2): 336–344; 364

Post-translational modifications (1): 495

Disulfide bonds (1): 159–194

Glycosylation sites (5): 139, 174, 178, 182, 209

Mutagenesis-validated functional residues (3):

Position	Phenotype
364	no induction of the mapk pathway.
484	gain of an autophosphorylation activity. gain of an autophosphorylation activity; when associated with a-359. gain of an
485	gain of an autophosphorylation activity. gain of an autophosphorylation activity; when associated with g-334 and f-481.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-201681	TCF dependent signaling in response to WNT
R-HSA-4086400	PCP/CE pathway
R-HSA-162582	Signal Transduction
R-HSA-195721	Signaling by WNT
R-HSA-3858494	Beta-catenin independent WNT signaling

MSigDB gene sets: 348 (showing top): GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_AXON_EXTENSION, GOBP_SYNAPSE_ASSEMBLY, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GCANCTGNY_MYOD_Q6, GOBP_NON_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GOBP_NEURON_PROJECTION_EXTENSION_INVOLVED_IN_NEURON_PROJECTION_GUIDANCE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEUROGENESIS

GO Biological Process (25): signal transduction (GO:0007165), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), axonogenesis (GO:0007409), axon guidance (GO:0007411), synapse assembly (GO:0007416), positive regulation of neuron projection development (GO:0010976), neurogenesis (GO:0022008), corpus callosum development (GO:0022038), neuron differentiation (GO:0030182), neuron projection development (GO:0031175), non-canonical Wnt signaling pathway (GO:0035567), chemorepulsion of dopaminergic neuron axon (GO:0036518), positive regulation of MAPK cascade (GO:0043410), skeletal system morphogenesis (GO:0048705), negative regulation of axon extension involved in axon guidance (GO:0048843), axon extension involved in axon guidance (GO:0048846), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), canonical Wnt signaling pathway (GO:0060070), Wnt signaling pathway, planar cell polarity pathway (GO:0060071), commissural neuron axon guidance (GO:0071679), positive regulation of cell proliferation in midbrain (GO:1904935), midbrain dopaminergic neuron differentiation (GO:1904948), protein phosphorylation (GO:0006468), Wnt signaling pathway (GO:0016055), negative chemotaxis (GO:0050919)

GO Molecular Function (12): protein kinase activity (GO:0004672), transmembrane signaling receptor activity (GO:0004888), frizzled binding (GO:0005109), ATP binding (GO:0005524), coreceptor activity (GO:0015026), Wnt-protein binding (GO:0017147), Wnt receptor activity (GO:0042813), nucleotide binding (GO:0000166), protein tyrosine kinase activity (GO:0004713), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020), signaling receptor complex (GO:0043235), presynaptic active zone membrane (GO:0048787), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Signaling by WNT	2
Beta-catenin independent WNT signaling	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
Wnt signaling pathway	3
nervous system development	2
cell differentiation	2
positive regulation of intracellular signal transduction	2
axon guidance	2
signaling receptor activity	2
cellular anatomical structure	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
enzyme-linked receptor protein signaling pathway	1
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
axonogenesis	1
neuron projection guidance	1
cell junction assembly	1
synapse organization	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
telencephalon development	1
anatomical structure development	1
generation of neurons	1
neuron development	1
plasma membrane bounded cell projection organization	1
dopaminergic neuron axon guidance	1
chemorepulsion of axon	1
MAPK cascade	1
regulation of MAPK cascade	1
skeletal system development	1
animal organ morphogenesis	1
negative regulation of axon extension	1
regulation of axon extension involved in axon guidance	1
axon extension involved in axon guidance	1
negative regulation of chemotaxis	1
axon extension	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1

Protein interactions and networks

STRING

1170 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RYK	WNT5A	P41221	995
RYK	WNT11	O96014	993
RYK	WNT7A	O00755	958
RYK	WNT3A	P56704	925
RYK	DVL1	O14640	908
RYK	WNT3	P56703	880
RYK	LRP5	O75197	863
RYK	WNT4	P56705	852
RYK	RORA	P35397	828
RYK	WNT1	P04628	824
RYK	WNT5B	Q9H1J7	790
RYK	WNT8B	Q93098	786
RYK	FZD1	Q9UP38	765
RYK	FZD4	Q9ULV1	755
RYK	WNT7B	P56706	733

IntAct

22 interactions, top by confidence:

A	B	Type	Score
TNFSF8	TOR1B	psi-mi:“MI:0914”(association)	0.640
MILR1	INPPL1	psi-mi:“MI:0914”(association)	0.640
RYK	PCDH7	psi-mi:“MI:0914”(association)	0.530
SLC39A5	TMEM223	psi-mi:“MI:0914”(association)	0.530
PPP3CA	RYK	psi-mi:“MI:0915”(physical association)	0.370
PPM1B	RYK	psi-mi:“MI:0915”(physical association)	0.370
PTPRR	RYK	psi-mi:“MI:0915”(physical association)	0.370
CFTR	SNHG32	psi-mi:“MI:0914”(association)	0.350
NCR3LG1	PEDS1	psi-mi:“MI:0914”(association)	0.350
SIGLECL1	RBFOX3	psi-mi:“MI:0914”(association)	0.350
PTH2R	METTL15	psi-mi:“MI:0914”(association)	0.350
PVR	QSOX1	psi-mi:“MI:0914”(association)	0.350
RAET1E	GOLIM4	psi-mi:“MI:0914”(association)	0.350
MICA	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
RYK	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
IGDCC4	SGCE	psi-mi:“MI:0914”(association)	0.350
CEACAM21	MET	psi-mi:“MI:0914”(association)	0.350
CDC37	MAP2K7	psi-mi:“MI:0914”(association)	0.350
RYK	DUSP14	psi-mi:“MI:0914”(association)	0.350
RYK	FAM171A2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (268): RYK (Affinity Capture-RNA), RYK (Affinity Capture-RNA), RYK (Affinity Capture-RNA), RYK (Affinity Capture-MS), RYK (Affinity Capture-MS), RYK (Affinity Capture-MS), RYK (Affinity Capture-MS), RYK (Affinity Capture-MS), RYK (Affinity Capture-MS), RYK (Affinity Capture-MS), RYK (Affinity Capture-MS), RYK (Affinity Capture-MS), RYK (Affinity Capture-MS), RYK (Affinity Capture-MS), RYK (Affinity Capture-MS)

ESM2 similar proteins: A0A8I5ZNK2, B1H3E1, D4AE59, O70293, O88506, P00535, P11273, P24786, P32298, P34925, P34947, P43250, P49137, P49138, P50904, P97711, Q01887, Q03351, Q0GGW5, Q15139, Q15831, Q16288, Q16644, Q3MHQ0, Q3SYZ2, Q3UMW7, Q59H18, Q5N942, Q5XIS9, Q62101, Q66H84, Q6P9R2, Q6ZI44, Q6ZWH5, Q7TQP6, Q7XQP4, Q7Y0B9, Q8BZ03, Q8NHH1, Q8QGV6

Diamond homologs: A0JM20, A0M8R7, A0M8S8, A1X150, F1QVU0, G3V9H8, O02466, O35346, P00519, P00520, P00521, P00522, P00529, P06213, P07949, P08069, P08581, P08941, P09760, P0DV84, P10447, P13368, P14617, P16056, P20806, P22182, P23049, P30530, P33497, P34152, P34925, P35546, P35590, P42684, P55144, P55146, P57097, P70451, P97523, P97793

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
RYK	up-regulates	DVL1	binding
RYK	up-regulates	DVL2	binding
RYK	up-regulates	DVL3	binding
WNT1	up-regulates	RYK	binding
WNT3A	up-regulates	RYK	binding
RYK	up-regulates	FZD8	binding
MIB1	down-regulates	RYK	ubiquitination
PSENEN	up-regulates	RYK	cleavage
WNT5A	up-regulates	RYK	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

44 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	13
Likely benign	5
Benign	11

Top pathogenic / likely-pathogenic (0)

SpliceAI

2510 predictions. Top by Δscore:

Variant	Effect	Δscore
3:134159229:AAACT:A	donor_loss	1.0000
3:134159230:AACTC:A	donor_loss	1.0000
3:134159231:ACT:A	donor_loss	1.0000
3:134159232:CTCAC:C	donor_loss	1.0000
3:134159233:TCA:T	donor_loss	1.0000
3:134159234:CA:C	donor_loss	1.0000
3:134159235:A:AC	donor_gain	1.0000
3:134159235:A:AT	donor_loss	1.0000
3:134159236:C:CT	donor_gain	1.0000
3:134159236:CA:C	donor_gain	1.0000
3:134159236:CAA:C	donor_gain	1.0000
3:134159236:CAAT:C	donor_gain	1.0000
3:134159236:CAATT:C	donor_gain	1.0000
3:134159369:GCCCA:G	acceptor_gain	1.0000
3:134159370:CCCA:C	acceptor_gain	1.0000
3:134159370:CCCAC:C	acceptor_gain	1.0000
3:134159371:CCA:C	acceptor_gain	1.0000
3:134159371:CCAC:C	acceptor_gain	1.0000
3:134159372:CA:C	acceptor_gain	1.0000
3:134159372:CAC:C	acceptor_gain	1.0000
3:134159373:ACT:A	acceptor_loss	1.0000
3:134159374:C:CC	acceptor_gain	1.0000
3:134159374:C:CG	acceptor_loss	1.0000
3:134159375:T:C	acceptor_loss	1.0000
3:134159377:G:C	acceptor_gain	1.0000
3:134159377:G:GC	acceptor_gain	1.0000
3:134159386:C:CT	acceptor_gain	1.0000
3:134175602:CACTT:C	donor_loss	1.0000
3:134175603:ACTTA:A	donor_loss	1.0000
3:134175605:TTA:T	donor_loss	1.0000

AlphaMissense

3993 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:134158180:A:C	F599L	1.000
3:134158180:A:T	F599L	1.000
3:134158181:A:C	F599C	1.000
3:134158181:A:G	F599S	1.000
3:134158182:A:G	F599L	1.000
3:134158190:A:G	L596P	1.000
3:134158202:A:G	L592P	1.000
3:134158217:G:T	P587H	1.000
3:134158218:G:A	P587S	1.000
3:134158219:C:A	R586S	1.000
3:134158219:C:G	R586S	1.000
3:134158220:C:A	R586M	1.000
3:134158220:C:G	R586T	1.000
3:134158221:T:A	R586W	1.000
3:134158240:C:A	W579C	1.000
3:134158240:C:G	W579C	1.000
3:134158241:C:G	W579S	1.000
3:134158242:A:G	W579R	1.000
3:134158242:A:T	W579R	1.000
3:134158243:G:C	C578W	1.000
3:134158244:C:T	C578Y	1.000
3:134158245:A:G	C578R	1.000
3:134158253:A:C	M575R	1.000
3:134158253:A:T	M575K	1.000
3:134158261:A:C	F572L	1.000
3:134158261:A:T	F572L	1.000
3:134158262:A:G	F572S	1.000
3:134158263:A:C	F572V	1.000
3:134158263:A:G	F572L	1.000
3:134158263:A:T	F572I	1.000

dbSNP variants (sampled 300 via entrez): RS1000066840 (3:134165552 C>A), RS1000115817 (3:134198282 A>T), RS1000134822 (3:134171396 C>A), RS1000164125 (3:134198254 T>A,C), RS1000181101 (3:134214040 C>T), RS1000244458 (3:134206894 T>A), RS1000263840 (3:134232066 A>G), RS1000269694 (3:134225734 G>A), RS1000288631 (3:134162568 C>G), RS1000323898 (3:134156800 G>A), RS1000340990 (3:134244229 C>T), RS1000359476 (3:134176940 C>A,T), RS1000400882 (3:134158319 T>C), RS1000452465 (3:134201058 G>T), RS1000497404 (3:134226425 G>A,T)

Disease associations

OMIM: gene MIM:600524 | disease phenotypes: MIM:119530

GenCC curated gene-disease

Mondo (1): orofacial cleft 1 (MONDO:0007335)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002936_17	Cadmium levels	9.000000e-06
GCST004279_13	Systolic blood pressure	1.000000e-11
GCST007094_105	Diastolic blood pressure	7.000000e-14
GCST007095_46	Systolic blood pressure	6.000000e-09
GCST007095_47	Systolic blood pressure	3.000000e-09
GCST007098_45	Diastolic blood pressure	6.000000e-12
GCST007098_46	Diastolic blood pressure	1.000000e-11
GCST007099_124	Systolic blood pressure	3.000000e-10
GCST007268_15	Diastolic blood pressure	9.000000e-09
GCST008839_554	Height	5.000000e-16
GCST011369_10	Iron status biomarkers (ferritin levels)	7.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0006336	diastolic blood pressure
EFO:0004459	ferritin measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566121	Orofacial Cleft 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Type XV RTKs: RYK

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	affects cotreatment, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
dicrotophos	decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
aflatoxin B2	increases methylation	1
ON 01910	decreases phosphorylation	1
Temozolomide	affects response to substance	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases expression	1
Vorinostat	increases expression	1
Ethanol	affects cotreatment, decreases expression, increases abundance	1
Atrazine	decreases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	increases expression	1
Coumestrol	decreases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Quercetin	decreases expression	1
Thiram	decreases expression	1
Valproic Acid	affects expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	decreases expression	1

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2EE	Abcam HeLa RYK KO	Cancer cell line	Female
CVCL_D8UX	Ubigene HCT 116 RYK KO	Cancer cell line	Male
CVCL_TJ91	HAP1 RYK (-) 1	Cancer cell line	Male
CVCL_TJ92	HAP1 RYK (-) 2	Cancer cell line	Male
CVCL_TJ93	HAP1 RYK (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.